While various reports have been made so far on a laboratory-scale method for synthesizing an alkoxyindanone derivative, there have been very few reports regarding its industrial production method.
For example, Non-Patent Document 1 discloses that 1 g of 3-(3,4-dimethoxyphenyl)propionic acid and 10 g of polyphosphoric acid were reacted at 65° C. for 25 minutes, followed by addition of cold water. Then, the resulting mixture was extracted with diethyl ether or ethyl acetate, and the organic layer thus extracted was washed with a 10% aqueous solution of sodium bicarbonate and purified by crystallization with ethanol to give 0.812 g (yield 90%) of 5,6-dimethoxy-1-indanone. However, it is also reported that the yield dropped to 71% when the reaction time was extended to 70 minutes in the above method. Generally, each unit operation is time-consuming in an industrial-scale production, and thus, it is difficult to perform operations in such a way that reactions are completed within only several tens of minutes. In view of the foregoing, the method described in the above document is far from an industrially efficient production method.
Further, Patent Document 1 discloses that 300 g of 3-(3,4-dimethoxyphenyl)propionic acid and 1500 g of polyphosphoric acid were reacted at 65° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was then cooled, to which 2000 mL of deionized water was then gradually added. The mixture was then stirred at room temperature for two hours and then extracted with 600 mL of chloroform six times. The organic layer thus extracted was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, and then filtrated. The filtrate thus obtained was concentrated to dryness under reduced pressure to give 170 g (yield 62%) of 5,6-dimethoxy-1-indanone. However, in this method, a reaction vessel of approximately 3 L or larger is needed to obtain only 170 g of a target compound. Therefore, the volumetric efficiency is low. Also, industrialization of the above method is difficult because chloroform, which is highly toxic to human bodies and the environment, is used as an extraction solvent.
Further, Patent Document 2 discloses that 3-chloropropionyl chloride was reacted with 1,2-dimethoxybenzene in the presence of aluminum chloride to produce 3-chloro-3′,4′-dimethoxypropiophenone in situ. To the reaction mixture concentrated sulfuric acid was added and the reaction was allowed to proceed at 70° C. The resulting product was then purified by silica gel column chromatography to give 5,6-dimethoxy-1-indanone with a yield of 40%. However, silica gel chromatography as used in the above method is a cumbersome method, and further, a problem of the above method is low yield.
According to Non-Patent Document 2, it is known that a method for producing an alkoxy compound using polyphosphoric acid as disclosed in Non-Patent Document 1 and Patent Document 1 is advantageous in that it does not cause a dealkylation reaction compared to a production method using aluminum chloride as disclosed in Patent Document 2. Accordingly, polyphosphoric acid is effective in order to obtain a quality alkoxyindanone derivative. However, as described above, a high yield cannot be anticipated unless the reaction time is as short as 25 to 30 minutes and a large amount of water is needed for decomposition of polyphosphoric acid, and also a large amount of highly toxic organic solvents is needed for extraction in the above method. Therefore, because facilities to be used and operational processes are increased when the production is carried out on an industrial scale by a conventional method, there are demerits that the production efficiency is low and large amounts of organic waste liquid and acid waste liquid are produced.
Non-Patent Document 1: J. Koo, J. Am. Chem. Soc., 75, 1891-1895 (1953)
Patent Document 1: JP Patent Publication (Kokai) No. 11-92427A (1999)
Patent Document 2: JP Patent Publication (Kokai) No. 11-302216A (1999)
Non-Patent Document 2: Edited by The Chemical Society of Japan, Experimental Chemistry, Vol. 18, a reaction of organic compounds II (the second half of the volume), 205-289 (1958)